National Human Genome Research Institute's vision for genomic medicine includes elements of both discovery and implementation. This vision seeks to improve the practice of medicine through the appropriate integration of genomic information into clinical care while continuing to better understand fundamentals of genomic variation, genome structure and the role of genetic variation in disease and therapeutic outcomes. The eMERGE network has made critical contributions to discovery by developing methods for high throughput electronic phenotyping using information captured in electronic health records (EHRs) in the course of clinical care and identifying new associations between diseases and quantitative traits with common genetic variants through genome wide associations studies. eMERGE has also provided leadership in implementing genomic medicine by developing interfaces with EHR, clinical decision support, strategies for holding genomic variant information and transferring clinically relevant variants into the EHR, and returning genomic variant information to physicians and patients, both for disease susceptibility and for improving therapeutic management, particularly with prescription and dosing of medications. In addition, development and dissemination of best practices for implementation has been an important goal of eMERGE. As a participant in both eMERGE I and II, Northwestern (NU) through its EHR-linked biobank NUgene, has made significant contributions to all of these activities, with several NU investigators playing key leadership roles. In this application we propose to leverage the infrastructure and expertise at NU to (a) discover associations between rare variants in at least 100 sequenced genes and common variants from the eMERGE GWAS dataset from phenotypes derived from EHR data mining, (b) enroll 2000 patients into the study who agree to receive genomic information and allow the information to be stored in their EHR, (c) return clinically actionable results to healthcare providers and patients to determine utility and clinical outcomes, and (d) develop and share best practices related to returning genomic results, educating physicians and patients, and the related ethical, legal and social implications. Successfully achieving these goals will provide new scientific knowledge and significant real world experience that will advance the NHGRI vision for both discovery and implementation across the spectrum of its strategic vision.